CH621552A5 - - Google Patents

Description

The present invention relates to a process for the preparation of substituted 1,3-dimethyl-lHrpyrazol- [3,4-b] -quinolines and pharmaceutically acceptable salts thereof, which are suitable, for example, as antiviral agents in mammals.

US Pat. No. 3,600,393 (Graeve et al.) Describes compounds of the formula hnch_ch_ch_nr, r ch and their pharmaceutically acceptable salts as compounds with hypocholesterolemic and hypolipemic activity. The reaction scheme described there is useful to prepare the general class of compounds used in the present invention.

Stein et al., J. Med. Chem. 13 153 (1970) describes, inter alia, that compounds which are 7-chloro-1,3-dimethyl-1H-pyrazole substituted with nitrogen in the 4-position [3 , 4b] quinolines, were examined with regard to their anti-malaria activity.

US Pat. No. 3,234,142 (Wolfrum et al.) Describes compounds which are substituted 1-methyl-3-alkyl-1H-pyrazole [3,4b] quinolines, but which do not contain nitrogen in the 4-position Bear substituents. The reaction scheme described is essentially a reaction scheme which can be used to form intermediate products which can be used in the process according to the invention.

It has been found that compounds of the formula

F

G

CH

J

where E is selected from hydrogen, lower alkoxy, lower alkylthio, hydroxy, thio, trifluoromethyl, lower

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like dialkylaminoalkoxy, amino, lower alkylamino and lower dialkylamino,

wherein F is selected from hydrogen, lower alkyl, lower alkoxy, lower alkylthio, hydroxy, thio, trifluoromethyl, lower dialkylaminoalkoxy, amino, lower alkylamino and lower dialkylamino,

wherein G is selected from hydrogen, lower alkyl, lower alkoxy, lower alkylthio, hydroxy, thio, trifluoromethyl, lower dialkylaminoalkoxy, amino, lower alkylamino and lower dialkylamino,

wherein J is selected from hydrogen, lower alkyl, lower alkoxy, lower alkylthio, hydroxy, thio, trifluoromethyl, lower dialkylaminoalkoxy, amino, lower alkylamino and lower dialkylamino,

where n represents an integer from 2 to 12,

wherein Y is selected from amino, lower alkylamino, lower dialkylamino and cyclically substituted amino in the form of a 5- or 6-membered heterocyclic saturated ring which optionally contains another nitrogen atom or an oxygen atom,

and wherein at least one of Groups E, F, G and J is other than hydrogen, or a pharmaceutically acceptable salt thereof, has antiviral activity in mammals.

The pharmaceutically acceptable, non-toxic salts include the organic and inorganic acid addition salts, for example those from acids such as hydrochloric acid, sulfuric acid, sulfonic acid, tartaric acid, fumaric acid, hydrobromic acid, hydroiodic acid, glycolic acid, citric acid, maleic acid, phosphoric acid, succinic acid, acetic acid and the like manufactured salts. Such salts can be prepared by customary methods by reacting the free base with the desired acid. The compounds described contain a variety of salt-forming groups and any or all of them can be combined with one or more acids to form acid salts.

The term "lower alkyl" used in the present invention means both straight-chain and branched alkyl radicals having 1 to 8 carbon atoms, for example methyl, ethyl, propyl, isopropyl, butyl and the like.

The preferred antiviral compounds obtainable according to the invention correspond to the formula

(D B (II)

B

C.

where A is hydrogen or lower alkoxy,

wherein B is selected from hydrogen, lower alkyl, lower alkoxy and lower alkylamino,

wherein C is selected from hydrogen, lower alkyl, 5 lower alkoxy and halogen,

where D is hydrogen or lower alkoxy,

wherein one or two of groups A, B, C and D are different from hydrogen,

wherein n represents an integer from 2 to 6 inclusive, io and where Y is selected from dimethylamino, amino, diethylamino, dipropylamino, methylamino, ethylamino, propylamino, tertiary butylamino and a cyclically substituted amino radical which is selected from

The compounds described, which have an antiviral activity, are prepared by mixing the correspondingly substituted 4-chloro-1,3-dimethyl-1H-pyrazole [3,4b] quinoline with an amine of the formula

H ^ ch ^ Y

implements. This reaction is conveniently carried out in the presence of a non-reactive solvent and at an elevated temperature. Suitable solvents include aromatic solvents such as toluene or xylene, or polar solvents such as N, N-dimethylformamide or N, N-dimethyl-acetamide. Alternatively, an excess of the amine can be used to serve as the solvent. The reaction is preferably carried out in the range from 100 ° to 200 ° C. Neither the temperature nor the solvent are so critical. The product can be obtained by conventional methods such as those listed below.

The compounds described above can generally be prepared according to a reaction scheme described in U.S. Patent 3,600,393 and exemplified below. The reaction scheme is as follows:

A O

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(II)

(III)

CH3NHNH.

acetic acid

(III)

(IV)

P0C1-

H.N- (CH) Y 2 2 n

(VI)

l.H2N (CH2) nOH 2.S0C12

HN (Œ2) nCl

While the above reaction scheme is generally required to prepare the compounds described above in which B represents an amino or substituted amino group, the compounds can be prepared according to the following reaction scheme:

(VII)

5

(Vili)

HN (CH2) nY

ch3

hno3 / h2so4 ^

CH-

hn (ch2) ny

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(Vili)

(XIII a)

H0; Pd / C

The amino group is then substituted to provide the desired substituted amino group, for example:

(ix)

(XIII b)

CH3-CNH

Acetic anhydride pyridine

An alternative way of producing the N- (3-methyl-5-pyrazolyl) anthranilic acid intermediates is a reaction of the Ullmann type according to the following reaction scheme: 45

(xii) a

C02M (H or metal)

X (I, Broder Cl)

hn (ch2) ny

h2n

CH-

HN (CH2) nY

ch-

Cu inert solvent

(III)

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6

In the above reaction (XII), M is preferably an Al potassium metal. The catalyst is a copper-containing catalyst; examples include copper powder, copper-bronze, copper-II-bromide, copper-II-oxide, copper-II-acetate and other copper-containing compounds. The reaction is preferably carried out in the presence of an inert solvent using heat sufficient to drive the reaction forward. Examples of suitable solvents include dimethylformamide, n-amyl alcohol, xylene, diethylene glycol dimethyl ether and water.

The invention is described in more detail in connection with the following examples and production methods of starting materials, which serve for illustration. All parts and percentages in the examples and production methods in the description relate to the weight, unless stated otherwise. In the following production methods and examples, the formulas given correspond to the NMR (nuclear magnetic resonance) and the IR (infrared) analysis of the materials.

Method A 2-Acetonyl-7-methyl-4H-3, l-benzoxazin-4-one

A mixture of 25.0 g (0.17 mol) of 4-methylanthranilic acid and 13.95 g (0.17 mol) of diketene in 250 ml of CCl4 is heated under reflux for 2.5 hours. 18.3 g (0.18 mol) of acetic anhydride are added and the mixture is stirred under reflux for 16 hours. The mixture is then cooled and the product is isolated by filtration. Upon recrystallization, 17.4 g (48%) of 2-acetonyl-7-methyl-4H-3, l-benzoxazin-4-one with a melting point of 142 ° to 144 ° C. are obtained. Analysis for: C12HuN03

calculated: C 66.35 H 5.10 N 6.45 found: C 66.14 H 5.23 N 6.39

Method B

N- (1,3-Dimethyl-5-pyrazolyl) -4-methylanthranilic acid

15.31 g (0.071 mol) of the benzoxazinone from method A is added to a solution of 3.90 g (0.085 mol) of methylhydrazine in 150 ml of acetic acid and the solution obtained is stirred at 80 ° C. for 2.5 hours. The solvent is removed and the product is recrystallized from acetonitrile, giving 8.59 g (49%) of N- (1,3-dimethyl-5-pyrazolyl) -4-methyl-anthranilic acid with a melting point of 188 to 192 ° C. .

Analysis for: C13H15N302

calculated: C 63.66 H 6.16 N 17.13 found: C 63.47 H 6.20 N 17.38

Method C N- (1,3-dimethyl-5-pyrazolyl) anthranilic acid

The catalyst used is prepared by briefly etching a commercially available copper powder (1 micron) in 1N aqueous hydrochloric acid. The powder is then filtered, washed with water and acetone and dried in the oven.

8.0 g of o-iodobenzoic acid, 3.88 g of 5-amino-1, 3-dimethylpyrazole and 0.8 g of the copper catalyst are added in succession to a solution of 4.84 g of potassium carbonate in 18 ml of water. The mixture is stirred under reflux for 5 hours. A further 50 ml of water are then added and the mixture is refluxed for a further 30 minutes and then filtered through diatomaceous earth. The filtrate is treated with decolorizing activated carbon, heated to reflux and filtered. The filtrate is cooled and acidified with 3N aqueous hydrochloric acid, giving N - (1,3-dimethyl-5-pyrazolyl) -anthranilic acid with a melting point of 175 to 189 ° C., which gives needles after recrystallization from ethanol melt at 204 to 206 ° C.

example 1

4- (3-dimethylaminopropylamino) -l, 3,7-trimethyl-1H-pyrazole3,4b] quinoline dihydrochloride

A mixture of 6.47 g (0.026 mol) of N- (1,3-dimethyl-5-pyrazolyl) -4-methyl-anthranilic acid and 65 ml of phosphorus oxychloride is stirred under reflux for 3 hours. The chilled mixture is concentrated at 5 mm to a syrup which is poured onto ice. The mixture is made basic with 4N NaOH and then extracted with chloroform. The chloroform extracts are washed, dried and evaporated to give 4.75 g of 4-chloro-1,3,7-trimethyl-1H-pyrazole- [3,4b] quinoline. The product is treated with 50 ml of 3-dimethylaminopropylamine and the mixture is stirred at reflux for 12 hours. The mixture is cooled and excess amine is evaporated at 5 mm. The residue is dissolved in chloroform and the solution obtained is washed successively with aqueous potassium carbonate, water and brine. Drying (Na2S04) and evaporation gives 6.86 g of product. Dissolving in 1-propanol and treating with 2 equivalents of aqueous In hydrochloric acid after evaporation gives 4- (3-dimethylaminopropylamino) -1,3,7-trimethyl-lH-pyrazole [3,4b] quinoline dihydrochloride; Recrystallization (aqueous ethanol) gives a product with a melting point of 290 ° to 293 ° C (dec.).

Analysis for: C1SH25N5. 2HC1

calculated: C 56.25 H 7.08 N 18.22 found: C 56.45 H 7.12 N 18.24

Example 2

1,3-Dimethyl-4- (4-dimethylaminobutylamino) -lH-pyrazole- [3,4bquinoline dihydrochloride

A mixture of 4.63 g (0.02 mol) of 4-chloro-1,3-dimethyl-1H-pyrazoI [3,4b] quinoline, 2.76 g (0.02 mol) of potassium carbonate and 2.23 g (0.02 mol) of 4-dimethylaminobutylamine in 60 ml of dimethylformamide (DMF) is stirred at 130 ° for 16 hours. The solvent is removed at 5 mm and the residue is partitioned between water and chloroform. The organic phase is separated off, washed with water, dried and evaporated, leaving 6.02 g (97%) of an oil. The dihydrochloride salt is prepared as described above; Recrystallization (ethanol) yields 1,3-dimethyl-4- (4-dimethylaminobutylamino) -1 H-pyr-azole [3,4b] quinoline dihydrochloride with melting point 294 ° C (dec.).

Analysis for: C, gH25N3. 2HC1

calculated: C 56.25 H 7.08 N 18.22 found: C 55.68 H 6.88 N 18.32

Example 3

a) 1,3-Dimethyl-4- (3-dimethylaminopropylamino) -6-nitro-1H-pyrazole [3,4bquinoline

A mixture of 1.2 ml of 70% nitric acid and 13.6 ml of 95% sulfuric acid is added dropwise over a period of 30 minutes at 5 ° C. to a solution of 4.91 g (0.017 mol) of 1,3-dimethyl-4 - (3-dimethylaminopropylamino) - 1H-pyrazole [3,4b] quinoline in 30 ml nitromethane was added. After the addition, the mixture is stirred at 10 to 20 ° C. for 2 hours and then diluted with cold water and neutralized with ammonium hydroxide. The product, 1.3-

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-Dimethyl-4- (3-dimethylaminopropylamino) -6-nitro-1H - pyrazole [3,4b] -quinoline is isolated by extraction in chloroform and worked up in the usual way. The yield is 4.61 g (82%) of product with a melting point of 189 to 192 ° C .; the dihydrochloride salt has a melting point of 262 to 264 ° C (dec.).

Analysis for: C17H22N602. 2HC1

calculated: C 49.17 H 5.83 N 20.23 found: C 48.54 H 6.02 N 20.08

b) 6-Amino-1,3-dimethyl-4- (3-dimethylaminopropylamino) - 1H-pyrazole [3,4bquinoline dihydrochloride 4.00 g (0.012 mol) of the nitro compound described above, which is suspended in 100 ml of ethanol containing 0.4 g of 5% Pd / C is shaken under hydrogen at an initial pressure of 3.52 kg / cm2 (50 psi) for 2.5 hours. The catalyst is removed by filtration and the solvent is evaporated, leaving the 6-amino-1,3-dimethyl-4 - (3-dimethylaminopropylamino) -IH-pyrazoI [3,4b] quinoline - dihydrochloride. It is necessary to store the compound under nitrogen as it quickly turns dark in the air. The compound is converted into the dihydrochloride salt in a conventional manner and recrystallized from ethanol. Melting point 305 ° C (dec.).

Analysis for: CI7H.MN,;. 2HCI

calculated: C 52.99 H 6.80 N 21.81 found: C 51.19 H 7.21 N 21.07

Example 4

6-acetamido-1,3-dimethyl-4- (3-dimethylaminopropylamino) -1 H-pyrazole [3,4bquinoline

1.85 g (0.0059 mol) of the amine described above in 30 ml of pyridine is treated with 0.61 g (0.0059 mol) of acetic anhydride and the solution is stirred at 28 ° C. for 16 hours. The solution is poured onto ice / water and treated with 4N aqueous NaOH and extracted with chloroform. Evaporation of the dried organic phase gives the 6-acetamido - 1,3-dimethyl-4- (3-dimethylaminopropylamino) -1H-pyrazoI- [3,4b] quinoline. Recrystallization from water gives a product with melting point 64 to 76 ° C (hydrated).

Analysis for: C19H20NuO

calculated: 'C 64.38 H 7.39 N 23.71 found: C 64.52 H 7.12 N 24.08 (corrected for 3.76% water of hydration)

Example 5

4- (3-dìme thylaminopropy lamino) -! , 3,6,7-tetramethyl-1 H -pyrazole [3,4b quinoline dihydrochloride

2.85 g (0.011 mol) of N- (1,3-dimethyl-5-pyrazolyI) -4,5-dimethylanthranilic acid and 60 ml of phosphorus oxychloride are stirred under reflux for 1.5 hours. The POCl3 is then evaporated and the residue is cooled, an excess (about 60 ml) of 3-dimethylaminopropylamine being added. The reaction mixture is then kept under reflux for 16 hours. The reaction mixture is then cooled and evaporated.

The residue is dissolved in chloroform and the solution obtained is washed successively with aqueous potassium carbonate, water and brine, dried with Na2S04 and evaporated to give 3.34 g of a yellow solid (94% yield). Dissolve in 1-propanol and heat with 2 equivalents of aqueous. In hydrochloric acid, after filtering and cooling to 4 ° C., the 4- (3-dimethylaminopropylamino) -l, 3,6,7-tetramethyl-lH-pyrazole

[3,4b] quinoline dihydrochloride in the form of white crystals with a melting point greater than 300 ° C.

Analysis for: C19H27N5. 2HC1

calculated: C 57.28 H 7.34 N 17.58 found: C 56.88 H 7.12 N 17.19

Example 6

1,3 ~ dimethyl-4- (3-dimethylaminopropylamino) -6-methoxy-1H-pyrazole [3,4b quinoline dihydrochloride

0.825 g (0.00316 mol) of 4-chloro-1,3-dimethyl-6-methoxy-1H-pyrazole f 3,4b] quinoline, which, as described above, consists of N- (1,3-dimethylpyrazolyl) -5 -methoxyanthranilic acid was mixed with approximately 10 ml of 3-dimethylaminopropylamine and refluxed for 16 hours. The product is cooled and extracted as described above, isolated and treated in 1-propanol with 2 equivalents in HCl and then evaporated. The solid is dissolved in hot ethanol and then cooled to 4 ° and stored until needle-like crystals form. It is filtered and the crystals are washed repeatedly with cold ethanol. The crystals are dried under vacuum; Melting point 281 to 282 ° C (dec.).

Analysis for: C18H25Nr, 0. 2HC1

calculated: C 54.00 H 6.80 N 17.49 found: C 53.87 H 6.49 N 17.51

Example 7

1,3-Dimethyl-4- (3-dimethylaminopropylamino) -7-ethyl-1H-pyrazole [3,4b quinoline dihydrochloride

A mixture of 5.00 g (0.0193 mol) of N- (1,3-dimethyl-5-pyrazolyl) -4-ethylanthranilic acid and 50 ml of phosphorus oxychloride is stirred under reflux for 2 hours. Excess POCl3 is then removed under reduced pressure and the residue is heated to 130 ° C. for 16 hours with 60 ml of 3-dimethylamino-propylamine. The excess amine is then removed under reduced pressure and the oily residue is taken up in chloroform, washed with aqueous sodium carbonate, water and brine, dried over Na2SO4 and the chloroform is evaporated to give 6.98 g of a tan oil.

The dihydrochloride salt is prepared as described above using 4.0N HCl. The crude solid salt is washed with acetone and recrystallized from n-propanol, then isopropanol, 5.25 g of white, solid 1,3-dimethyl-4- (1,3-dimethylaminopropylamino) -7-ethyl-1H- pyrazole [3,4b] quinoline dihydrochloride with melting point 248 to 251 ° C (dec.)

Analysis for: ClnH27N5. 2HC1

calculated: C 57.29 H 7.34 N 17.58 found: C 57.20 H 7.61 N 17.62

Example 8

1,3-dimethyl-4- (3-dimethylaminopropylamino) -6.7 - dimethoxy-1H-pyrazole 3.4b quinoline dihydrochloride

A mixture of 7.0 g (0.0241 mol) of N- (1,3-dimethyl-5-pyrazolyl) -4,5-dimethoxyanthranilic acid and 100 ml of phosphorus oxychloride is stirred under reflux for 3 hours, cooled and the excess POCl3 is removed under reduced pressure. The solid obtained is heated with 100 ml of 3-dimethylamino-propylamine to 174 ° C. for 18 hours. The cooled reaction mixture is between a large volume of aqueous sodium carbonate and chloroform

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distributed. The organic layer is then washed with water and brine, dried over Na2S04 and evaporated to give 5.0 g of semicrystalline material, which is triturated under cold ether and filtered. The filtrate is concentrated to remove the solvent to give 3.55 g of a viscous oil which is applied to 75 g of alumina on a column and eluted with 500 ml of 95/5 ether / ethanol. The eluate is evaporated to dryness to give 2.10 g of an oil which partially crystallizes on standing. This material is rubbed under a minimal amount of cold ether and filtered to give 753 g of a sticky solid. The dihydrochloride salt is prepared as previously described. Melting point 259 to 261 ° C (dec.).

Analysis for: C19H27N502. 2HC1

calculated: C 53.03 H 6.79 N 16.27 found: C 53.55 H 6.66 N 15.90

Example 9

4- (3-dimethylaminopropylamino) -1, 3,6-trimethyl-1H-pyrazole [3,4bquinoline dihydrochloride

A mixture of 3.70 g (0.0151 mol) of N- (1,3-dimethyl-5-pyrazolyl) -5-methylanthranilic acid and 65 ml of phosphorus oxychloride is stirred under reflux for 3 hours.

After removing the excess POCl3, an excess of 3-dimethylaminopropylamine is added and the mixture is kept under reflux for 16 hours. The excess amine is then removed and the product is extracted with chloroform, washed and isolated as described above to give 4.59 g of a yellow solid. The product dissolved in 1-propanol is treated with 2 equivalents in aqueous HCl to form the dihydrochloride, which is isolated by evaporation. The product is recrystallized from ethanol, giving 4.06 g of white, solid 4- (3-dimethylaminopropylamino) -l, 3,6-trime-thyI-1H-pyrazole [3,4b] quinoline dihydrochloride with a melting point of 274 ° C. (Dec.) Receives.

Analysis for: C, 8H25Nn. 2HC1

calculated: C 56.25 H 7.08 N 18.22 found: C 57.75 H 6.62 N 18.48 The following compounds are prepared in the manner described in the general reaction schemes and the preceding examples:

Example 10

1,3-Dimethyl-4- (3-dimethylaminopropyllamino) -5-methoxy-- lH-pyrazole [3,4bquinoline dihydrochloride

Recrystallized from aqueous ethanol; Melting point 278 ° C (dec.).

Analysis for: C18H25N50. 2HC1

calculated: C 54.00 H 6.80 N 17.49 found: C 54.17 H 6.72 N 17.43

Example 11

1,3-Dimethyl-4- (2-dimethylaminoethylamino) -lH-pyrazole- [3,4b] quinoline dihydrochloride

Recrystallized from aqueous ethanol; Melting point greater than 300 ° C.

Analysis for: C, BH21N5. 2HC1

calculated: C 53.94 H 6.51 N 19.66 found: C 54.10 H 6.38 N 19.98

Example 12

1,3-Dimethyl-4- (5-dimethylaminopentylamino) -lH-pyrazole [3,4b quinoline dihydrochloride

5 recrystallized from 'ethanol; Melting point 268 to 271 ° C (dec.).

Analysis for: C19H2TN5. 2HC1

calculated: C 57.28 H 7.38 N 17.58 found: C 57.09 H 7.05 N 17.68

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Example 13

1,3-Dimethyl-4- (6-dimethylaminohexylamino) -lH-pyrazole- [3,4b J-quinoline-dihydrochloride 1,3-dimethyl-4- (3-methylaminopropylamino) -lH-pyrazole- [3,4b] -quinoline dihydrochloride

1,3-dimethyl-4- (3-aminopropylamino) -IH-pyrazole [3,4bJ-quinoline dihydrochloride

35 Recrystallized from ethanol, melting point 311 to 314 ° C (dec.).

Analysis for: C15H19N5. 2HC1

calculated: C 52.64 H 6.19 N 20.46 found: C 52.45 H 6.33 N 20.60

40

Example 16

1,3-dimethyl-4- (3-dimethylaminopropylamino) -8-methoxy-1H-pyrazole [3,4bquinoline dihydrochloride 1,3-dimethyl-4- (3-dimethylaminopropylamino) -7-methoxy-1H- pyrazole [3,4b quinoline dihydrochloride

55 Recrystallized from ethanol, melting point 261 to 263 ° C.

Analysis for: C18H25N50. 2HC1

calculated: C 54.00 H 6.80 N 17.49 found: C 53.85 H 7.19 N 17.63

60

Example 18

1,3-dimethyl-4- (3-dimethylaminopropylamino) -5,7-

dimethoxy-1H-pyrazole [3,4b] quinoline dihydrochloride

65 Recrystallized from ethanol, melting point 285 ° C (dec.).

Analysis for: C10H27N5O2. 2HC1

calculated: C 53.03 H 6.79 N 16.27 found: C 52.96 H 6.93 N 16.44

15 recrystallized from ethanol; Melting point 215 to 219 ° C (dec.).

Analysis for: C20H29N5. 2HC1

calculated: C 58.25 H 7.58 N 16.99

found: C 58.32 H 7.74 N 16.83

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Example 14

25 Recrystallized from ethanol, melting point 307 to 309 ° C (dec.).

Analysis for: C10H21N5. 2HC1

calculated: C 53.94 H 6.51 N 19.66

found: C 54.20 H 6.58 N 19.70

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Example 15

45 Recrystallized from ethanol, melting point 261.5 to 263 ° C (dec.).

Analysis for: C1SH2SN50. 2HC1

calculated: C 54.00 H 6.80 N 17.49

found: C 54.26 H 7.03 N 17.90

50

Example 17

9

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The compounds obtainable according to the invention show an antiviral activity which makes them valuable as antiviral agents in mammals. The compounds exhibit interferon-inducing activity in either p.o. or I. p. Administration to mice.

The compounds according to Examples 1 and 9 have been found in tail lesions which were caused in mice (50 mg / kg orally) by vaccinia virus according to the method of Boyle et al., "Antimicrobial Agents and Chemotherapy" (1966) 536-539 (1967) , proven to be effective. In particular, the compound was administered at any time 6 to 24 hours before the insult with virus. The vaccinia virus, IHD strain, was introduced into the animals via the tail vein in a dose sufficient to cause 20 to 30 tail lesions per mouse. The lesions were counted after 7 days. A lesion reduction of more than 50% was considered significant.

The interferon elicitation tests, summarized in the table below, were carried out as follows: Various concentrations of the compounds, as indicated, were administered orally or intraperitoneally to 15 gram female CD-1 mice (Charles River Breeding Laboratories). Approximately 16 to 18 hours later, blood was drawn from the animals, the serum was collected and assayed in mouse L cells for the ability to prevent subsequent infection by vesicular stomatitis virus or mouse picornavirus GD-7. Vergi, see Siminoff et al., "Antimicrobial Agents and Chemotherapy" 3, 742-743 (1973) and Baron et al., "Science" 141, 15 1061-1063 (1963).

In the table below, a "+" means activity, a "±" low activity and a "-" lack of significant activity. "T" means toxicity.

Interferon activity p. o. (mg / kg) i. p. (mg / kg)

400 100 300 100

4- (3-dimethylaminopropylamino) -l, 3,7-trimethyl-lH-

pyrazole [3,4b] quinoline dihydrochloride (Example 1) 4- 4- T 4-4- (3-dimethylaminopropylamino) -l, 3,6-trimethyl-lH-

-pyrazole [3,4b] quinoline dihydrochloride (Example 9) 4- 4- T 4-4- (3-dimethylaminopropylamino) -l, 3,6,7-tetramethyl-lH-

-pyrazole [3,4b] quinoline dihydrochloride (Example 5) 4-4-l, 3-dimethyl-4- (3-dimethylaminopropylamino) -6) 7-di-

methoxy-1H-pyrazole [3,4b] quinoline dihydrochloride (Example 8) 4-4-

1,3-Dimethyl-4- (3-dimethylaminopropylamino) -5,7-di-methoxy-1H-pyrazole [3,4b] quinoline dihydrochloride

(Example 18) 4- 4-l, 3-dimethyl-4- (3-dimethylaminopropylamino) -6-methoxy-

-lH-pyrazoi [3,4b] quinoline dihydrochloride (Example 6) 4- ± 4- ± 1,3-dimethyl-4- (3-dimethylaminopropylamino) -5-methoxy-

-lH-pyrazole [3,4b] quinoline dihydrochloride (Example 10) 4-4-4-4-l, 3-dimethyl-4- (3-dimethylaminopropylamino) -7-methoxy-

-lH-pyrazole [3,4b] quinoline dihydrochloride (Example 17) ± 4-4-4-l, 3-dimethyl-4- (3-dimethylaminopropylamino) -8-methoxy-

-lH-pyrazoi [3,4b] quinoline dihydrochloride (Example 16) 4-4-4-

1,3-DimethyI-4- (2-dimethylaminoethylamino) -lH-pyrazoI- [3,4b] quinoline dihydrochloride (Example 11) ± -

1,3-dimethyl-4- (4-dimethylaminobutylamino) - 1H-pyrazole-

[3,4b] quinoin dihydrochloride (Example 2) 4- -

1,3-dimethyl-4- (5-dimethylaminopentylamino) - 1H-pyrazole-

L3,4b] quinoline dihydrochloride (Example 12) 4- ± 4- ±

1,3-dimethyl-4- (6-dimethylaminohexylamino) -1 H-pyrazole-

[3,4b] quinoline dihydrochloride (Example 13) 4- -

1,3-dimethyl-4- (3-methylaminopropylamino) -lH-pyrazole-

[3,4b] quinoline dihydrochloride (Example 14) 4- - 4- -

1,3-dimethyl-4- (3-N-methylpiperazine) -1 H-pyrazole [3,4b] -

quinoline dihydrochloride (Example 5) 4- ± 4- ±

1,3-dimethyl-4- (3-aminopropylamino) -lH-pyrazole [3,4b] -

quinoline dihydrochloride (Example 15) 4- - 4- - •

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Interferon activity p. o. (mg / kg) i. p. (mg / kg)

400 100 300 100

1,3-dimethyl-4- (3-dimethy laminopropylamino) -7-ethyl-1H-

-pyrazole [3,4b] quinoline dihydrochloride (Example 7) T +

1,3-dimethyl-4- (3-dimethylaminopröpyIamino) -lH-pyrazole-

[3,4b] quinoline dihydrochloride + - + ±

4- (3-dimethylaminopropylamino) -l, 3,7,8-tetramethyl-lH-

-pyrazole [3,4b] quinoline dihydrochloride + ±

4- (3-dimethylaminopropylamino) -l, 3,6,8-tetramethyl-lH-

-pyrazole [3,4b] -quinoline dihydrochloride + -

The compounds obtainable according to the invention can trigger the synthesis and the release of interferon, as a result of which they act as prophylactic and therapeutic agents in the prevention and / or treatment of viral infections, in particular by viruses from the group virus vaccinia, virus vesicular stomatitis or picornavirus, in mammals, including humans.

The compounds can be administered to humans in a dosage in the range of 50 to 2000 mg three to four times a day, depending on the weight of the patient and the route of administration.

Claims (2)

621552 2nd PATENT CLAIMS 1. Process for the preparation of compounds of the formula CH wherein E is selected from hydrogen, lower alkoxy, lower alkylthio, hydroxy, thio, trifluoromethyl, lower dialkylaminoalkoxy, amino, lower alkylamino and lower dialkylamino, wherein F is selected from hydrogen, lower alkyl, lower alkoxy, hydroxy, lower alkylthio, thio, trifluoromethyl, lower dialkylaminoalkoxy, amino, lower alkylamino and lower dialkylamino, wherein G is selected from hydrogen, lower alkyl, lower alkoxy, hydroxy, lower alkylthio, thio, trifluoromethyl, lower dialkylaminoalkoxy, amino, lower alkylamino and lower dialkylamino, where J is selected from hydrogen, lower alkyl, lower alkoxy, hydroxy, lower alkylthio, thio, trifluoromethyl, lower dialkylaminoalkoxy, amino, lower alkylamino and lower dialkylamino, where n is an integer from 2 to 12, wherein Y is selected from amino, lower alkylamino, lower dialkylamino and cyclically substituted amino in the form of a 5- or 6-membered, optionally containing a further nitrogen atom or an oxygen atom, saturated heterocyclic ring, and in which at least one of the groups E, F, G and J is different from hydrogen, or from pharmaceutically acceptable salts thereof, characterized in that a 4-chloro-1,3-dimethyl-1H-pyrazole [3,4blquinoline of the formula Cl ch with an amine of the formula H ^ CH ^ Y implements. 2. The method according to claim 1, characterized in that one carries out the reaction in the presence of a non-reactive solvent, preferably at an elevated temperature. 3. Process for the preparation of a compound of the formula ch h_c-c-nh I. ch3 wherein n and Y have the meanings given in claim 1, or of pharmaceutically acceptable salts thereof, characterized in that a compound of the formula ch N 2nd ch acetylated.